Tetrandrine family pharmaceutical formulations and method

ABSTRACT

Drug formulations, methods and their use in treatment of diseases using formulations of pure di-acid salts of tetrandrine family members, especially d-tetrandrine di-hydrochloride, combined with a pharmaceutical diluent or carrier.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication No. 61/792,849, entitled TETRANDRINE FAMILY PHARMACEUTICALFORMULATIONS AND METHOD, filed on Mar. 15, 2013, the entire contents ofwhich are incorporated by reference.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to pharmaceutical formulations of a familyof bisbenzylisoquinoline alkaloids. The specific family is referred toherein as the “tetrandrine family.”

The tetrandrine family bisbenzylisoquinolines have two nitrogenlocations and hence can exist in the free base form or as a mono ordi-acid salt. Because of the enhanced solubility of the salt form ofpharmaceutical ingredients, the salt forms are used in formulatingpharmaceutical compositions. The active ingredient thus solubilizes morequickly and enters the bloodstream faster.

However, the di-acid chlorides of the tetrandrine family members, mostimportantly the dihydrochloride (DHC), are a difficult molecule toproduce using standard pharmaceutical processing. As a result, all knownformulators in the world use an in situ procedure as part of thecompounding methodology. This leads to variations in content uniformityand tablet-to-tablet potency variances.

SUMMARY OF THE INVENTION

The present invention uses pure di-acid salts of tetrandrine familymembers, preferably d-tetrandrine, and most preferably d-tetrandrinedi-hydrochloride, in pharmaceutical formulations. In a preferredembodiment, the di-acid salts are formed by spray drying. As usedherein, the term “pure di-acid salt of a tetrandrine family member”means greater than 99% pure on an anhydrous basis.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The tetrandrine family members have been found effective in treatingmulti-drug resistance in a variety of diseases and conditions, includingcancer and malaria. See U.S. Pat. Nos. 5,025,020; 5,332,747; 6,528,519;6,911,454; 6,124,315 and 6,962,927. The formulation of these activeingredients into suitable pharmaceutical delivery systems is thus veryimportant.

The tetrandrine family members have the following structural formula:

Where R₁ and R₁′ are the same or different shortchained carbon basedligand including without limitation, CH₃, CO₂CH₃ or H; and R₂ is CH₃ orC₂H₅; and R₃ is CH₃ or hydrogen; and where the chemical structurepreferably has the “S” isomeric configuration at the C-1′ chiral carbonlocation.

The preferred members of the tetrandrine family include the followingrepresentative examples, which are not intended to be exhaustive:d-tetrandrine, isotetrandrine, hernandezine, berbamine, pycnamine,phaeanthine, obamegine, ethyl fangchinoline and fangchinoline. In all ofthese examples, R₁ and R₁′ constitute the methyl group. Variation withinthe group occurs in that R₂ and R₃ may constitute either a methyl groupor hydrogen, and the isometric configuration of the compounds at the C-1and C-1′ chiral carbon positions is either R (rectus) or S (sinister).The rules for R and S configuration can be found in Morrison and Boyd,“Organic Chemistry,” ^(4th) Edition, copyright 1983 by Allyn and Bacon,at pp. 138-141. In addition, hernandezine includes a methoxy group atthe C-5 position.

The most preferred member of the claimed tetrandrine family isd-tetrandrine. Methods for extracting and/or purifying d-tetrandrine aredisclosed in U.S. Pat. No. 6,218,541 and in Published Patent ApplicationNo. 2011/0105755.

The di-acid salt of the tetrandrine family member is made by dissolvinga purified member of the tetrandrine family, preferably d-tetrandrine,in exactly 2 molar equivalents of dilute acid, preferably hydrochloricacid (5-20% molar) in a vessel. The resulting clear solution is filteredto remove any residual solids into a glass feeding vessel. The solutionis tested to assure that the potency of di-acid is within the specifiedlimits. A spray drier is set with a wall temperature of 240-400 C. Theatomizer is set to feed the di-acid salt solution at a rate of 1-2liters/minute. The spray dried di-acid salt is captured in a poly baglined container to yield 90-95% of the assayed di-acid salt in the feedsolution. The solid di-acid salt is tested and released for formulationinto capsules, though other dosage forms can be used. The di-acid saltused is preferably prepared from 99.9% pure tetrandrine family member,using exactly 2 equivalents of hydrochloric acid. The resulting soliddi-acid salt contains only residual water and substantially no otherimpurities. As used herein, the term “pure di-acid salt of a tetrandrinefamily member” means greater than 99% pure on an anhydrous basis.

The dosage level used in humans will vary from case to case. However, itis anticipated that one would typically administer the tetrandrinefamily member drug at from about 50 to about 1000 mg per square meterper day, more preferably 250-700, and most preferably about 500, forfrom about 4 to about 14 days, during the course of treatment with aprinciple drug for treating the disease being treated.

The tetrandrine family members have known applications as primary orsolo use drugs, as for example in the treatment of malaria, and inreducing hypertension. However, they are also known for use inconjunction with other drugs. The ratio of the tetrandrine family memberto a principle or secondary drug will also vary from patient to patient,and from drug to drug, within a range of from about 0.04:1 to about170:1. A more typical range would be from about 1:1 to 100:1, morepreferably from 25:75 to 75:25.

The preferred formulations comprise a di-acid salt member of thed-tetrandrine family combined with a suitable pharmaceutical carrier.The pharmaceutical carrier can be a liquid or a solid composition. Aliquid carrier will preferably comprise water, possibly with additionalingredients such as 0.25% carboxymethylcellulose. The solid carrier ordiluent used is preferably pregelatinized starch. It may also beformulated with other ingredients, such as colloidal silicone dioxide,sodium lauryl sulfate and magnesium stearate.

Exemplary capsule formulations include the following:

-   -   50 mg d-Tetrandrine di-hydrochloride    -   384 mg Pregelatinized Starch NF (Starch 1500)    -   4.4 mg Colloidal Silicon Dioxide (Cab-O-Sil M5)    -   0.4 mg Sodium Lauryl Sulfate NF    -   1.0 mg Magnesium Stearate NF;    -   100 mg d-Tetrandrine di-hydrochloride    -   70 mg microcrystalline cellulose    -   0.2 mg sodium lauryl sulfate    -   0.6 mg magnesium stearate; and    -   200 mg d-Tetrandrine di-hydrochloride    -   25.2 mg Pregelatinized Starch 1500 NF    -   1.5 mg Silicon Dioxide USP    -   0.25 mg Sodium Lauryl Sulfate NF    -   1.25 mg Magnesium Stearate USP.        Although the d-tetrandrine used in these formulations is the        di-hydrochloride, the 50, 100 and 200 mg weights used the free        base weights. Thus the actual amount of active used was slightly        greater than the 50, 100 and 200 mgs indicated.

The 200 mg capsule formulation is most preferred. The most preferreddose of about 500 mg/square meter/day is roughly 1000 mg per day for a190 pound patient six feet tall. Such a patient can fulfill the dosagerequirements by taking five capsules during the course of the day, forexample three in the morning and two in the evening, or one at a timespaced out over the day. A woman weighing 125 pounds at a height of fivefeet six inches would require four 200 mg capsules during the course ofthe day.

The various diseases which have been treated using tetrandrine familymembers in conjunction with principle drugs for treating the diseases,and the principle drugs used, are disclosed in U.S. Pat. Nos. 5,025,020;5,332,747; 6,528,519; 6,911,454; 6,124,315 and 6,962,927.

Of course, it is understood that the forgoing are preferred embodimentsof the invention, and that variations can be employed without departingfrom the spirit of the invention as set forth in the appended claims,interpreted in accordance with the principles of patent law.

The invention claimed is:
 1. A pharmaceutical formulation comprising:the pure di-acid salt of d-tetrandrine combined with a pregelatinizedstarch carrier, colloidal silicone dioxide, sodium lauryl sulfate andmagnesium stearate in the following amounts: 50 mg d-tetrandrine di-acidsalt, 384 mg Pregelatinized Starch NF (Starch 1500), 4.4 mg ColloidalSilicon Dioxide (Cab-O-Sil M5), 0.4 mg Sodium Lauryl Sulfate NF, and 1mg Magnesium Stearate NF.
 2. A pharmaceutical formulation comprising:the pure di-acid salt of d-tetrandrine combined with a pregelatinizedstarch carrier, colloidal silicone dioxide, sodium lauryl sulfate andmagnesium stearate in the following amounts: 200 mg d-tetrandrinedi-acid salt, 25.2 mg Pregelatinized Starch 1500 NF, 1.5 mg SiliconDioxide USP, 0.25 mg Sodium Lauryl Sulfate NF, and 1.25 mg MagnesiumStearate USP.
 3. A pharmaceutical formulation comprising: the puredi-acid salt of d-tetrandrine combined with a pregelatinized starchcarrier, microcrystalline cellulose, sodium lauryl sulfate and magnesiumstearate in the following amounts: 100 mg d-tetrandrine di-acid salt, 70mg microcrystalline cellulose, 0.2 mg sodium lauryl sulfate, and 0.6 mgmagnesium stearate.